Genome-wide association study of germline variants and breast cancer-specific mortality.
Maria Escala-Garcia,
Qi Guo,
Thilo Dörk,
Sander Canisius,
Renske Keeman,
Joe Dennis,
Jonathan Beesley,
Julie Lecarpentier,
Manjeet K Bolla,
Qin Wang,
Jean Abraham,
Irene L Andrulis,
Hoda Anton-Culver,
Volker Arndt,
Paul L Auer,
Matthias W Beckmann,
Sabine Behrens,
Javier Benitez,
Marina Bermisheva,
Leslie Bernstein,
Carl Blomqvist,
Bram Boeckx,
Stig E Bojesen,
Bernardo Bonanni,
Anne-Lise Børresen-Dale,
Hiltrud Brauch,
Hermann Brenner,
Adam Brentnall,
Louise Brinton,
Per Broberg,
Ian W Brock,
Sara Y Brucker,
Barbara Burwinkel,
Carlos Caldas,
Trinidad Caldés,
Daniele Campa,
Federico Canzian,
Angel Carracedo,
Brian D Carter,
Jose E Castelao,
Jenny Chang-Claude,
Stephen J Chanock,
Georgia Chenevix-Trench,
Ting-Yuan David Cheng,
Suet-Feung Chin,
Christine L Clarke,
,
Emilie Cordina-Duverger,
Fergus J Couch,
David G Cox,
Angela Cox,
Simon S Cross,
Kamila Czene,
Mary B Daly,
Peter Devilee,
Janet A Dunn,
Alison M Dunning,
Lorraine Durcan,
Miriam Dwek,
Helena M Earl,
Arif B Ekici,
A Heather Eliassen,
Carolina Ellberg,
Christoph Engel,
Mikael Eriksson,
D Gareth Evans,
Jonine Figueroa,
Dieter Flesch-Janys,
Henrik Flyger,
Marike Gabrielson,
Manuela Gago-Dominguez,
Eva Galle,
Susan M Gapstur,
Montserrat García-Closas,
José A García-Sáenz,
Mia M Gaudet,
Angela George,
Vassilios Georgoulias,
Graham G Giles,
Gord Glendon,
David E Goldgar,
Anna González-Neira,
Grethe I Grenaker Alnæs,
Mervi Grip,
Pascal Guénel,
Lothar Haeberle,
Eric Hahnen,
Christopher A Haiman,
Niclas Håkansson,
Per Hall,
Ute Hamann,
Susan Hankinson,
Elaine F Harkness,
Patricia A Harrington,
Steven N Hart,
Jaana M Hartikainen,
Alexander Hein,
Peter Hillemanns,
Louise Hiller,
Bernd Holleczek,
Antoinette Hollestelle,
Maartje J Hooning,
Robert N Hoover,
John L Hopper,
Anthony Howell,
Guanmengqian Huang,
Keith Humphreys,
David J Hunter,
Wolfgang Janni,
Esther M John,
Michael E Jones,
Arja Jukkola-Vuorinen,
Audrey Jung,
Rudolf Kaaks,
Maria Kabisch,
Katarzyna Kaczmarek,
Michael J Kerin,
Sofia Khan,
Elza Khusnutdinova,
Johanna I Kiiski,
Cari M Kitahara,
Julia A Knight,
Yon-Dschun Ko,
Linetta B Koppert,
Veli-Matti Kosma,
Peter Kraft,
Vessela N Kristensen,
Ute Krüger,
Tabea Kühl,
Diether Lambrechts,
Loic Le Marchand,
Eunjung Lee,
Flavio Lejbkowicz,
Lian Li,
Annika Lindblom,
Sara Lindström,
Martha Linet,
Jolanta Lissowska,
Wing-Yee Lo,
Sibylle Loibl,
Jan Lubiński,
Michael P Lux,
Robert J MacInnis,
Melanie Maierthaler,
Tom Maishman,
Enes Makalic,
Arto Mannermaa,
Mehdi Manoochehri,
Siranoush Manoukian,
Sara Margolin,
Maria Elena Martinez,
Dimitrios Mavroudis,
Catriona McLean,
Alfons Meindl,
Pooja Middha,
Nicola Miller,
Roger L Milne,
Fernando Moreno,
Anna Marie Mulligan,
Claire Mulot,
Rami Nassir,
Susan L Neuhausen,
William T Newman,
Sune F Nielsen,
Børge G Nordestgaard,
Aaron Norman,
Håkan Olsson,
Nick Orr,
V Shane Pankratz,
Tjoung-Won Park-Simon,
Jose I A Perez,
Clara Pérez-Barrios,
Paolo Peterlongo,
Christos Petridis,
Mila Pinchev,
Karoliona Prajzendanc,
Ross Prentice,
Nadege Presneau,
Darya Prokofieva,
Katri Pylkäs,
Brigitte Rack,
Paolo Radice,
Dhanya Ramachandran,
Gadi Rennert,
Hedy S Rennert,
Valerie Rhenius,
Atocha Romero,
Rebecca Roylance,
Emmanouil Saloustros,
Elinor J Sawyer,
Daniel F Schmidt,
Rita K Schmutzler,
Andreas Schneeweiss,
Minouk J Schoemaker,
Fredrick Schumacher,
Lukas Schwentner,
Rodney J Scott,
Christopher Scott,
Caroline Seynaeve,
Mitul Shah,
Jacques Simard,
Ann Smeets,
Christof Sohn,
Melissa C Southey,
Anthony J Swerdlow,
Aline Talhouk,
Rulla M Tamimi,
William J Tapper,
Manuel R Teixeira,
Maria Tengström,
Mary Beth Terry,
Kathrin Thöne,
Rob A E M Tollenaar,
Ian Tomlinson,
Diana Torres,
Thérèse Truong,
Constance Turman,
Clare Turnbull,
Hans-Ulrich Ulmer,
Michael Untch,
Celine Vachon,
Christi J van Asperen,
Ans M W van den Ouweland,
Elke M van Veen,
Camilla Wendt,
Alice S Whittemore,
Walter Willett,
Robert Winqvist,
Alicja Wolk,
Xiaohong R Yang,
Yan Zhang,
Douglas F Easton,
Peter A Fasching,
Heli Nevanlinna,
Diana M Eccles,
Paul D P Pharoah,
Marjanka K Schmidt
Abstract
METHODS
Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP).
CONCLUSIONS
We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.
RESULTS
We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10-8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10-7, hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10-7, HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster.
BACKGROUND
We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry.